CA1095032A - Mono-deuterated, 15-hydroxyprostaglandins - Google Patents
Mono-deuterated, 15-hydroxyprostaglandinsInfo
- Publication number
- CA1095032A CA1095032A CA255,572A CA255572A CA1095032A CA 1095032 A CA1095032 A CA 1095032A CA 255572 A CA255572 A CA 255572A CA 1095032 A CA1095032 A CA 1095032A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
- C07D307/937—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans with hydrocarbon or substituted hydrocarbon radicals directly attached in position 2, e.g. prostacyclins
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
Abstract of the Disclosure This invention provides new mono-deuterated prostaglandins having prolonged uterotonic activity.
Description
~L0~03~ r case 10 MONO-DEUTERATED,15-HYDROXYPROSTAGLANDINS
The present invention relates to deuterated prostaglandins and intermediates for their production.
It is to be appreciated that the present prostaglandings an2 intermediates are non-radioactive in the sense that they do not contain, e.g. hydrogen, atoms containing more than the nat~ral amount o~ radioactive isotopes, e.g. triti~.
In particul2r, the present invention provides mono-deuterated, 15-hvdroxy group-containing prostaglandins, the deuterium atom beins attached to the carbon atom in the 15-position. Such prcs~2slancins m2~ be in race~ic form or op,icall~ active form.
The present invention also provides a process for the production of such mono-deuterated, 15-hydroxy group-containins prostaalandins, which comprises splitting off the prGteCting croup or groups in a corresponding prosta-slandin having a deuterium ato-~ attached to the carbon atom in the 15-position and in which at least one hydro~
and/or carboxylic acid aroup is protected.
In a more particular aspect the present invention provides compouncs of fon~ula I, A ~ i C
D OH
I
~og5032 ].00-~361 wherein A is a group of formula O O
Al A2 or A4 A5 A~
B is a group of formula COX ' ~ N - N
Bl B2 N- N
COX or ~ COX
wherein X is hydroxy, al~oxy of 1 to 10 carbon atoms, lysergyloxy, lysergylamino or dihydrolyser-gylamino, and C is a prostaglandin end group.
10~032 100-43Gl A is pre~erably A2, ~3 or A4.
B is preferably Bl or B4. X is preferably hydroxy or alko~y. When ~ is alkoxy it is preferably of 1 to 4 carbon atoms, especially methoxy or ethoxy.In B4 it is to ~e appreciated that the substituents of the cyclopropyl ring are trans to each other.
C is a prostaglandin end group which corresponds to that of a natural or syr.thetic-prostaglandin. In particu]ar C may be a hydrocaxbyl group conveniently containing up to 16 carbon atoms which may con~ain a cyclic moiety and~or may contain unsaturation and/or may contain a ~-- heteroatom, such as oxygen. Prostaglandin end groups which are contemplated .include a) alkyl of 1 to 16 atoms, par~icularly a group Rl R2 /~ ~
- wherein Rl and ~2 are independently ~ydrogen or alkyl of 1 to 4 carbon atoms, b) a group 1 ~ 2 ~O~S03Z
w'nerein ~1 and R2 are as defined above, Z is -CH2- or -0-, R3 is hydrogen, fluorine, chlorine or trifluoromethyi, c) alkenyl of 3 to 10 carbon atoms, or d) cycloalkyl of 3 to 10 carbon atoms ~hlch is unsubstituted or substituted by alkyl cf up to 6 carbon atom~s.
C is preferably C a) as defined above. Rl and/or R2 when alkyl are preferably of 1 or 2 carbon atoms, especially methyl. When one f ~1 and R2 is alkyl and the other of Rl and R2 is hydrogen, the 15 carbon atom may have the R or S configuration.
It will be appreciaied that D stands for deuterium.
As indicated by the wa~7y lines in formula I tre hydroxy group attached to the 15-carbon ato~ may have the ~- or ~-configuration.
As indicated by the bro~en lines in formula I, the 5 and 6 carbon atoms may be linked by a single bond or a cis double bond, and the 13 and 14 carbon atoms 2Q may be linked by a single bond or a trans double bond.
The present invention further provides a process for the production of a compound of formula I as defined above, by splitti~g off with acid an acid sensitive protecting group or grou~s ~resen' in a co~ound of formula II, ~503Z , 00-4361 I II
A ~ ~
wherein A is A as defined above, or HO .
or O'R OR5 wherein R4 and R5 are, independently, hydrogen or an acid sensitive protecting ~roup, B is B as defined above, or COOR6 or - ~D~ ' wherein R6 is an acid sensitive protecting group, and C is as d~fined above, with the proviso that there is present at least one acid sensitive protecting group.
lO~S~3Z 100-4~61 The deprote~ting process as deiined above may be effected in conventional manner for such reactions.
Prefexably the protecting group is a group stable to basic conditions. Suitable groups include tetrahydro-pyranyl and tert.-butyldimethylsilyl. Suitable conditions are well known in the art, e.g. acetic acid/tetrahydro-furan/water; methanol/hydrochloric acid; sulphuric acid;
acetone/hydrochloric acid. Suitable temperatures are from -10 to 50C, preferably room temperature.
It will be appreciated that the prostaglandins of formulae I and II may be interconverted into other prostaglandins of formulae I and II respectivelyr e.g.
in conventional ~anner for such reactions.
For example, lysergyl esters, lysergyl amides and dihydro-lysergylamides may be made in conventional manner for producing such esters and amides, e.g~ as in Example 32.
Additionally, the moiety A2 may be changed into a moiety A6 by reaction with imidazole in conventional manner for the addition of an amine to the double bond of an ~,~
unsaturated ketone. Suitable conditions include reacting with imidazole at room temperature over several days. The imidazole may be in free form or the form of carbonyldi- -imidazole. ~urther reaction conditions are apparent from Example 33 which it is appreciated involves both ester formation and conversion from moiety A2 into A6.
'10~03~
100-~361 The compounds of formula II may also be prepared in conventiollal manner. ~or example a compound of formula III, E ~ III
wherein E is Ho H HO ~ H H~o ~ Y
~'' O , ~., El OR5 and R4, R5 and C are as defined above, may be reacted under Wittig conditions with a compound of formula IV, p~ ~
( 6 5)3 - CH - B IV
wherein B is as defined above, with, if desired, further reaction of the resulting product according to methods known in the prostaglandin art, e~g. selective oxidation at the 9 position.
A compound of formula III, 2s defined above, may be produced by selectively reducing the lactone moiety ~ in a compound of formula V, 7 ~
10~3~ 100-~361 F ~ C
V
D OR~
wherein C is as defined above, o , ~ is O
O~
~ 0~
Fl F2 OR5 . R~ and R5 are as defined above, in conventional manner, e.g. using diisobutylaluminium hydride.
The invention further provides a process for the production of a compound of formula V, which comprises deuterating a compound of formula VI, \ ~ ~ VI
wherein C is as defined above, and F is F1, F2, F3 or ~0~503Z loo-~ 361 ,' wherein P~7 is hydrogen or a bulky group capable of inrluencing the proportion of ~:~ alcohol formed, and if necessary converting any group R7 present into a group R5 as defined above, and if desired protecting the 3-hydroxy group with an acid sensitive protecting group.
The reaction may be carried out in conventional manner ~for such deuterations bearing in mind the other groups present. For example a deuterating agent such a5 sodium or zinc borodeuteride may be used. An anhydrous inert organic solvent such as dimethyl formamide or dimethoxyethane may be present. Suitable tempera~ures are bet~een ~40 and 50C. Preferably the reaction is effected under an inert gas atmosphere.
The ~- and ~-alcohols which may both be formed may be s~parated in conventional manner.
The group R7 may be chosen such that it influences by virtue of its size the proportion of a:B alcohol formed generally increasing the amount of ~-alcohol.
10~503Z loo-~ 3~]
Such ~roups are well known ill the art.
An e~ample of a suitable protecting group R7 i~
para-phenylbenzoyl or benzoyl. Such groups are split off under alkaline conditions, and may be exhanged for a group RS in conventional manner.
The 3-hydroxy group may be protected in conventional manner.
Free forms of prostaglandins being suitably basic, e.g. a compound of formula I, wherein A is A6, or X is lysergyloxy, lysergylamino or dihydrolysergylamino, may be converted into acid addition salt forms in conventional manner and vice versa. A suitable acid is methanesulphonic acid. Free forms of prostaglandins being suitably acidic, e.g. a compound of formula I, wherein X is hydroxy, may be converted into cationic salt forms in ccnventional manner and vice versa. A suitable cation is the sodilm~ cation.
Insofar as the production of any starting material is not particularly described these compounds are known, or may be produced and purified in accordance with known ~0 processes, or in a manner analogous tc processes described herein, e.g. in the Ex~amples, or to known processes.
It will be appreciated that optically active products may be obtcined from optically active starting materials.
10~5032 loo-~ 3~;1 The deutexa~ed pLostaalandins of the inven~ion, D especially the compounds of formula I~e~nibit interesting pharmacological activity. In particular the deuterated prostaglandins exhibit the same type of activity as the non-deuterated analogues, but have a longer duration of action. Thus the compounds of formula I in general, and especially the PGE and PGF~ compounds exhibit uterotonic activity, as indicated by a uterotonic effect on the rat uterus ln situ according to the principles of Bisset G.W. et al, Memoirs of the Society for Endocrinology No. 14 - Endogenous substances affecting the myometrium.
Edited by W.R. Pickles and R.J. Fitzpatrick, Cambridg~
University frey 1966, p. 185-198.
The deuterated prostaglandins may be administered in the same way and at the same dosage as the nor.-deuterated analogue~. An indicated daily dose for the uterotonic effect is from about 0.1 to about 20 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.02 to about 10 mg of the compound or in sustained release form. If the prostaglandin is suitably basic a pharmacologically acceptable acid addition salt form may be used. If the prostaglandin is suitably acidic a pharmacologically acceptable cationic salt form may be u5ed. Such salt forms are readily made in conventional manner from the 10~503Z loo--~ 361 free form and exhibit the same order of activ,it~ as the free form. Accordingly the present invention also provides a pharmaceutical composition comprising a mono-deuterated 15-hydroxy group-containing prostaglandin, the deuterium atom being attached to the carbon atom in the 15 position, or a compound of formula I, in association with a pharma-ceutical carrier or diluent. Such compositions may be formulated in conventional manner so as to be, for example, a solution or tablet, A group of compounds of formulae I and V comprises those whexein C is Cl wherein Rl and R2 are independently hydrogen or methyl, or C2 wherein Z is O and R3 is p- or m-fluoro- or p- or m-chloro or m-trifluoromethyl.
In the following Examples all temperatures are in degrees Centigrade and are uncorrected.
I.R. refers to characteristic bands exhibited in the infra-red spectrum of a methylene chloride solution.
10~5032 100-4361 EXAMPIE 1: 15 ~eutero-ll~ 15R-dih~drox~-16,16-dimeth~
9-~eto-2,3-(~)-trans-methylene-~rosta-5cis, ___________.__.__________ _____,._ _________ 13tlans-dlenoic acld ~00 mg of 15-deu';ero-lla,15~-bis-tetrahydro-pyranyloxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-5cis,13trans-dienoic acid tert.-butyldimethyl silyl ester is dissolved in 18 ml of a mixture of equal parts by volume of acetic acid, tetrahydrofuran, and water. The reaction mixture is maintained for 38 hours at room temperature, and then evaporated under a vacuum.
The residue is chromatographed on silica gel using - chloroform ~ 2% methanol as eluant to yield the pure title compound.
IR 3550, 3~00, 1720, 16~5 cn 1 lS In analogous manner to that described in Example 1 the following compounds of formula I are obtained from the corresponding 15-tetrahydropyranyl ether. When there is an ll-hydroxy group present in the final product the starting material is the appropriate 11,15-bis-tetra-hydropyranyl ether. When there is a 9-keto group and a carbonyl group present in the final product the carboxyl group is protected as the tert.-butyldimethyl silyl ester in the starting materiali otherwise the free acid is used as the starting materialqror the production of a final compound having a carboxyl group.
~0 ~t-30 3 ~
E~ 5PI.E 2: 15-Deutero~16,16-dimethyl-2,3-(+)-trans-methylene-9~ ,15R-trihydroxy-prosta-5cis, 13trans-dienoic acid.
I~ 3600, 3400, 1695 cm .
EXA~IPLE 3: 15-Deutero-11~,15R-dihydroxy-16,16-dimethyl-_ 9-keto-2,3-(+)-trans-methylene-prosta-5cis, 13trans-dienoic acid.
IR 3600, 3450, 1740l 1695 cm EXAl'~PLE 4: 15-Deutero-16,16-dimethyl-15R-hydroxy-2,3-0 (t) -trans-methylene-9-keto-prosta-5cis,10, 13trans-trienoic acid.
IR 3600, 1700, 1140 cm EXAMPLE 5: 15-Deutero-16,16-dimethyl-2,3-(~)-trans-methylene-9a,11a,15R-trihydroxy-prosta-5cis, 13trans-dienoic acid methyl ester.
IR 3600, 3400, 1720, 1710 cm XA~LE 6: 15-Deutero-16,16-dimRthyl-2,3-(-)-trans-methylene~9a,11a,15R-trihydroxy-prosta-5cis, 13trans-dienoic acid.
IR 3600, 3500, 1715, 1700 cm ~0~?5i032 100-~361 EXA_5~Lr 7: 15-Deutero-16,16-dimethyl--2,3~ trans-methylelle-9~x,11(~,15 ~ trlhydroxy-prosta-13-trans-enoic acid.
IR 3550 - 3400, 1700 cm EXAMPLE 8: 15-Deutero-lla,15R-dihydroxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-13 trans-enoic acid.
IR 3600 - 3400, 1740r 1695 cm EXA~5PLE 9: 15-Deutero-16,16-dimethyl-15R-hydroxy-9-keto-
The present invention relates to deuterated prostaglandins and intermediates for their production.
It is to be appreciated that the present prostaglandings an2 intermediates are non-radioactive in the sense that they do not contain, e.g. hydrogen, atoms containing more than the nat~ral amount o~ radioactive isotopes, e.g. triti~.
In particul2r, the present invention provides mono-deuterated, 15-hvdroxy group-containing prostaglandins, the deuterium atom beins attached to the carbon atom in the 15-position. Such prcs~2slancins m2~ be in race~ic form or op,icall~ active form.
The present invention also provides a process for the production of such mono-deuterated, 15-hydroxy group-containins prostaalandins, which comprises splitting off the prGteCting croup or groups in a corresponding prosta-slandin having a deuterium ato-~ attached to the carbon atom in the 15-position and in which at least one hydro~
and/or carboxylic acid aroup is protected.
In a more particular aspect the present invention provides compouncs of fon~ula I, A ~ i C
D OH
I
~og5032 ].00-~361 wherein A is a group of formula O O
Al A2 or A4 A5 A~
B is a group of formula COX ' ~ N - N
Bl B2 N- N
COX or ~ COX
wherein X is hydroxy, al~oxy of 1 to 10 carbon atoms, lysergyloxy, lysergylamino or dihydrolyser-gylamino, and C is a prostaglandin end group.
10~032 100-43Gl A is pre~erably A2, ~3 or A4.
B is preferably Bl or B4. X is preferably hydroxy or alko~y. When ~ is alkoxy it is preferably of 1 to 4 carbon atoms, especially methoxy or ethoxy.In B4 it is to ~e appreciated that the substituents of the cyclopropyl ring are trans to each other.
C is a prostaglandin end group which corresponds to that of a natural or syr.thetic-prostaglandin. In particu]ar C may be a hydrocaxbyl group conveniently containing up to 16 carbon atoms which may con~ain a cyclic moiety and~or may contain unsaturation and/or may contain a ~-- heteroatom, such as oxygen. Prostaglandin end groups which are contemplated .include a) alkyl of 1 to 16 atoms, par~icularly a group Rl R2 /~ ~
- wherein Rl and ~2 are independently ~ydrogen or alkyl of 1 to 4 carbon atoms, b) a group 1 ~ 2 ~O~S03Z
w'nerein ~1 and R2 are as defined above, Z is -CH2- or -0-, R3 is hydrogen, fluorine, chlorine or trifluoromethyi, c) alkenyl of 3 to 10 carbon atoms, or d) cycloalkyl of 3 to 10 carbon atoms ~hlch is unsubstituted or substituted by alkyl cf up to 6 carbon atom~s.
C is preferably C a) as defined above. Rl and/or R2 when alkyl are preferably of 1 or 2 carbon atoms, especially methyl. When one f ~1 and R2 is alkyl and the other of Rl and R2 is hydrogen, the 15 carbon atom may have the R or S configuration.
It will be appreciaied that D stands for deuterium.
As indicated by the wa~7y lines in formula I tre hydroxy group attached to the 15-carbon ato~ may have the ~- or ~-configuration.
As indicated by the bro~en lines in formula I, the 5 and 6 carbon atoms may be linked by a single bond or a cis double bond, and the 13 and 14 carbon atoms 2Q may be linked by a single bond or a trans double bond.
The present invention further provides a process for the production of a compound of formula I as defined above, by splitti~g off with acid an acid sensitive protecting group or grou~s ~resen' in a co~ound of formula II, ~503Z , 00-4361 I II
A ~ ~
wherein A is A as defined above, or HO .
or O'R OR5 wherein R4 and R5 are, independently, hydrogen or an acid sensitive protecting ~roup, B is B as defined above, or COOR6 or - ~D~ ' wherein R6 is an acid sensitive protecting group, and C is as d~fined above, with the proviso that there is present at least one acid sensitive protecting group.
lO~S~3Z 100-4~61 The deprote~ting process as deiined above may be effected in conventional manner for such reactions.
Prefexably the protecting group is a group stable to basic conditions. Suitable groups include tetrahydro-pyranyl and tert.-butyldimethylsilyl. Suitable conditions are well known in the art, e.g. acetic acid/tetrahydro-furan/water; methanol/hydrochloric acid; sulphuric acid;
acetone/hydrochloric acid. Suitable temperatures are from -10 to 50C, preferably room temperature.
It will be appreciated that the prostaglandins of formulae I and II may be interconverted into other prostaglandins of formulae I and II respectivelyr e.g.
in conventional ~anner for such reactions.
For example, lysergyl esters, lysergyl amides and dihydro-lysergylamides may be made in conventional manner for producing such esters and amides, e.g~ as in Example 32.
Additionally, the moiety A2 may be changed into a moiety A6 by reaction with imidazole in conventional manner for the addition of an amine to the double bond of an ~,~
unsaturated ketone. Suitable conditions include reacting with imidazole at room temperature over several days. The imidazole may be in free form or the form of carbonyldi- -imidazole. ~urther reaction conditions are apparent from Example 33 which it is appreciated involves both ester formation and conversion from moiety A2 into A6.
'10~03~
100-~361 The compounds of formula II may also be prepared in conventiollal manner. ~or example a compound of formula III, E ~ III
wherein E is Ho H HO ~ H H~o ~ Y
~'' O , ~., El OR5 and R4, R5 and C are as defined above, may be reacted under Wittig conditions with a compound of formula IV, p~ ~
( 6 5)3 - CH - B IV
wherein B is as defined above, with, if desired, further reaction of the resulting product according to methods known in the prostaglandin art, e~g. selective oxidation at the 9 position.
A compound of formula III, 2s defined above, may be produced by selectively reducing the lactone moiety ~ in a compound of formula V, 7 ~
10~3~ 100-~361 F ~ C
V
D OR~
wherein C is as defined above, o , ~ is O
O~
~ 0~
Fl F2 OR5 . R~ and R5 are as defined above, in conventional manner, e.g. using diisobutylaluminium hydride.
The invention further provides a process for the production of a compound of formula V, which comprises deuterating a compound of formula VI, \ ~ ~ VI
wherein C is as defined above, and F is F1, F2, F3 or ~0~503Z loo-~ 361 ,' wherein P~7 is hydrogen or a bulky group capable of inrluencing the proportion of ~:~ alcohol formed, and if necessary converting any group R7 present into a group R5 as defined above, and if desired protecting the 3-hydroxy group with an acid sensitive protecting group.
The reaction may be carried out in conventional manner ~for such deuterations bearing in mind the other groups present. For example a deuterating agent such a5 sodium or zinc borodeuteride may be used. An anhydrous inert organic solvent such as dimethyl formamide or dimethoxyethane may be present. Suitable tempera~ures are bet~een ~40 and 50C. Preferably the reaction is effected under an inert gas atmosphere.
The ~- and ~-alcohols which may both be formed may be s~parated in conventional manner.
The group R7 may be chosen such that it influences by virtue of its size the proportion of a:B alcohol formed generally increasing the amount of ~-alcohol.
10~503Z loo-~ 3~]
Such ~roups are well known ill the art.
An e~ample of a suitable protecting group R7 i~
para-phenylbenzoyl or benzoyl. Such groups are split off under alkaline conditions, and may be exhanged for a group RS in conventional manner.
The 3-hydroxy group may be protected in conventional manner.
Free forms of prostaglandins being suitably basic, e.g. a compound of formula I, wherein A is A6, or X is lysergyloxy, lysergylamino or dihydrolysergylamino, may be converted into acid addition salt forms in conventional manner and vice versa. A suitable acid is methanesulphonic acid. Free forms of prostaglandins being suitably acidic, e.g. a compound of formula I, wherein X is hydroxy, may be converted into cationic salt forms in ccnventional manner and vice versa. A suitable cation is the sodilm~ cation.
Insofar as the production of any starting material is not particularly described these compounds are known, or may be produced and purified in accordance with known ~0 processes, or in a manner analogous tc processes described herein, e.g. in the Ex~amples, or to known processes.
It will be appreciated that optically active products may be obtcined from optically active starting materials.
10~5032 loo-~ 3~;1 The deutexa~ed pLostaalandins of the inven~ion, D especially the compounds of formula I~e~nibit interesting pharmacological activity. In particular the deuterated prostaglandins exhibit the same type of activity as the non-deuterated analogues, but have a longer duration of action. Thus the compounds of formula I in general, and especially the PGE and PGF~ compounds exhibit uterotonic activity, as indicated by a uterotonic effect on the rat uterus ln situ according to the principles of Bisset G.W. et al, Memoirs of the Society for Endocrinology No. 14 - Endogenous substances affecting the myometrium.
Edited by W.R. Pickles and R.J. Fitzpatrick, Cambridg~
University frey 1966, p. 185-198.
The deuterated prostaglandins may be administered in the same way and at the same dosage as the nor.-deuterated analogue~. An indicated daily dose for the uterotonic effect is from about 0.1 to about 20 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.02 to about 10 mg of the compound or in sustained release form. If the prostaglandin is suitably basic a pharmacologically acceptable acid addition salt form may be used. If the prostaglandin is suitably acidic a pharmacologically acceptable cationic salt form may be u5ed. Such salt forms are readily made in conventional manner from the 10~503Z loo--~ 361 free form and exhibit the same order of activ,it~ as the free form. Accordingly the present invention also provides a pharmaceutical composition comprising a mono-deuterated 15-hydroxy group-containing prostaglandin, the deuterium atom being attached to the carbon atom in the 15 position, or a compound of formula I, in association with a pharma-ceutical carrier or diluent. Such compositions may be formulated in conventional manner so as to be, for example, a solution or tablet, A group of compounds of formulae I and V comprises those whexein C is Cl wherein Rl and R2 are independently hydrogen or methyl, or C2 wherein Z is O and R3 is p- or m-fluoro- or p- or m-chloro or m-trifluoromethyl.
In the following Examples all temperatures are in degrees Centigrade and are uncorrected.
I.R. refers to characteristic bands exhibited in the infra-red spectrum of a methylene chloride solution.
10~5032 100-4361 EXAMPIE 1: 15 ~eutero-ll~ 15R-dih~drox~-16,16-dimeth~
9-~eto-2,3-(~)-trans-methylene-~rosta-5cis, ___________.__.__________ _____,._ _________ 13tlans-dlenoic acld ~00 mg of 15-deu';ero-lla,15~-bis-tetrahydro-pyranyloxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-5cis,13trans-dienoic acid tert.-butyldimethyl silyl ester is dissolved in 18 ml of a mixture of equal parts by volume of acetic acid, tetrahydrofuran, and water. The reaction mixture is maintained for 38 hours at room temperature, and then evaporated under a vacuum.
The residue is chromatographed on silica gel using - chloroform ~ 2% methanol as eluant to yield the pure title compound.
IR 3550, 3~00, 1720, 16~5 cn 1 lS In analogous manner to that described in Example 1 the following compounds of formula I are obtained from the corresponding 15-tetrahydropyranyl ether. When there is an ll-hydroxy group present in the final product the starting material is the appropriate 11,15-bis-tetra-hydropyranyl ether. When there is a 9-keto group and a carbonyl group present in the final product the carboxyl group is protected as the tert.-butyldimethyl silyl ester in the starting materiali otherwise the free acid is used as the starting materialqror the production of a final compound having a carboxyl group.
~0 ~t-30 3 ~
E~ 5PI.E 2: 15-Deutero~16,16-dimethyl-2,3-(+)-trans-methylene-9~ ,15R-trihydroxy-prosta-5cis, 13trans-dienoic acid.
I~ 3600, 3400, 1695 cm .
EXA~IPLE 3: 15-Deutero-11~,15R-dihydroxy-16,16-dimethyl-_ 9-keto-2,3-(+)-trans-methylene-prosta-5cis, 13trans-dienoic acid.
IR 3600, 3450, 1740l 1695 cm EXAl'~PLE 4: 15-Deutero-16,16-dimethyl-15R-hydroxy-2,3-0 (t) -trans-methylene-9-keto-prosta-5cis,10, 13trans-trienoic acid.
IR 3600, 1700, 1140 cm EXAMPLE 5: 15-Deutero-16,16-dimethyl-2,3-(~)-trans-methylene-9a,11a,15R-trihydroxy-prosta-5cis, 13trans-dienoic acid methyl ester.
IR 3600, 3400, 1720, 1710 cm XA~LE 6: 15-Deutero-16,16-dimRthyl-2,3-(-)-trans-methylene~9a,11a,15R-trihydroxy-prosta-5cis, 13trans-dienoic acid.
IR 3600, 3500, 1715, 1700 cm ~0~?5i032 100-~361 EXA_5~Lr 7: 15-Deutero-16,16-dimethyl--2,3~ trans-methylelle-9~x,11(~,15 ~ trlhydroxy-prosta-13-trans-enoic acid.
IR 3550 - 3400, 1700 cm EXAMPLE 8: 15-Deutero-lla,15R-dihydroxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-13 trans-enoic acid.
IR 3600 - 3400, 1740r 1695 cm EXA~5PLE 9: 15-Deutero-16,16-dimethyl-15R-hydroxy-9-keto-
2,3 (-)-trans-methylene-prosta-10,13trans-dienoic acid.
IR 3600, 1700 cm YAMPLE 10. 15-Deutero-2-ethylene-16,16-dimethyl-9~,lla, 15R-trihydroxy-prosta-5cis,13trans-dienoic acid.
IR 3400, 1690 cm 1.
EXA~PLE 11: 15-Deutero-2-ethylene-16,16-dimethyl-11~,15R-dihydroxy-9-keto-prosta-5cis,13trans-dienoic acid.
20 IR 3400, 1740-- 1730, 1700 - 1680 cm EY~IPLE 12: 15-Deutero-2-ethylene-16,16-dimethyl-15R-hydroxy-9-keto-prota-5cis,10,13trans-trienoic acid~
IR 3600, 1710 - 1685 cm ~0~503~ 100-43~1 ~XArlPT~ 13: 16-n butyl-15-deutero-2,3-(-)-trans-methylene-9~ 15S-trihydroxy- -prosta-5cis,13trans dienoic acid IR 3550 - 3350, 1715 - 1680 cm EY~lPLE 14: 16-n-butyl-15-deutero-11~,15S-dihydroxy-9-keto-2,3-(-)-trar,s-methylene-prosta-5cis, 13trans-dienoic acid.
IR 3550 - 3350, 1745 - 1690 cm EXAMPLE 15: 16-n-butyl-15-deutero-15S-hydroxy-9-keto-(2,3)-(-)-trans-methylene-prosta-5cis,10,13 trans-trienoic acid.
IR 3600, 1745 - 1690 cm EXAMPLE 16: 15-Deutero-lla,15R-dihydroxy-9-keto-16R-methyl-2,3-(-)-trans-methylene-prostanoic acid.
IR 3600 - 3300, 1740 - 1690 em EYAMPLE 17: 15-Deutero-lla,15R-dihydroxy-9-keto-16R-methyl-2,3-(-)-trans-methylene-prosta-5cis-enoic acid.
IR 3600 - 3350j 1735 - 1685 em EXAMPLE 18: 15-Deutero-11~,15R-dihydroxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-5cis, 13trans dienoic acid methyl ester.
IR 3600 - 3400, 1750 - 1700 cm ~0~5032 100-~361 EXAMPLE 19: 15-Deutero-16jl6-dimethyl-9~ a,lSR-trihydro~y--__ _ 17 t 18/19,20-tetranor-16-(3' trifluoromethyl-phenoxy)-2,3-(-)-trans-methylene-prosta--5cis, 13trans-dienoic acid.
IR 3500 - 3300, 1730 - 1670 cm EXA~LE 20: 1-Descarboxy-15-deutero 16,16--dimethyl-2-(5'-tetrazolyl)-9a,11a,15R-trihydroxy-17,18, 19,20-tetranor-16-(3'-trifluoromethylphenoxy)-prosta-5cis,13trans-dienoic acid.
IR 3500 - 3300 cm EXAMPLE 21: 15-Deutero-lla,15 R -dihydroxy-16,16-dimethyl-2,3-(-)-trans-methylene-9-keto-17,18,19,20-tetranor-16-(3'-trifluoromethylpheno~y)-prosta-5cis,13trans-dienoic acid.
IR 3500 - 3300, 1760 - 1720, 1720 - 1670 cm EXAMPLE 22: 15-Deutero-9a~11a,15S-trihydroxy-prosta-5cis, 13trans-dienoic acid lysergyl ester.
IR 3550 - 3400, 1740 (broad).
EXAMPLE 23: 15-Deutero-15S-hydroxy-ll~imidazol-l'-yl-9-keto-prosta-5cis,13trans-dienoic acid (l'-dècanyl) ester.
IR 3550 - 3350, 1740, 1720 cm 100-~36l F.XA~IPLE 24: 15-Deutero-15S-hydroxy~ imida~ol -l'-yl-9-keto-prosta-13-trans-enoic acid lysergyl ester.
IR 3500 - 3400, 1745, 1725, 1505 cm EXA~IPLE 2_: 15-Deutero~ ,15S-dihydroxy-9-keto-prosta-13trans-enoic acid lysergyl ~mide.
IR (CH2C12 + 1% CH30H) 3400 ~broad), 1745, 1665, 1525 cm EXAMPLE_ 26: 15-Deutero-16,16-dimethyl-9a,11a,15R-trihydroxy-prosta~5cis,13trans~dienoic acid IR 3650 - 3300, 1750 - 1700 cm EX~PLE 27: 15-Deutero-lla,15R-dihydroxy-16,16-dimethyl 9~keto-prosta-5cis,13trans-dienoic acid IR 3600 - 3300, 1760 - 1710, 1710 - 1630 cm EXAMPLE 28: (~)-15-Deutero-15~^hydroxy--9-ketoprostanoic acid.
IR 3550, 1760 - 1700 cm EXAMPLE 29: ~+)-15-Deutero-17,18,19,20-tetranor-16-[3'-tri-fluoromethylphenoxy]-9a,11a,15~-hydroxy-pros'a--5cis,13trans-dienoic acid.
IR 36Q0, 3350, 1710 cm EXAMPLE 30: 15-Deutero-11~,15R-dihydroxy-9-keto-16R-methyl-prosta-5cis enoic acid methyl ester.
IR 3700 - 3300, 1740 cm 1.
-- 1~ --~0~ 50~2 loo - ~ 3Gl ExAr~lPLE 31: 15-Deutero-11~,15S~dihydroxy-9-keto-prost2-5cis,13trans-dienoic acid lysergyl ester.
IR 1740 ~broad) cm Preparation of starting materials, e.g. for Example 1.
a) (-)-2R-~3'~deutero-3'a-hvdroxv~4r,4'-dimethyl-trans-1'-OCteIlyl ~ -50;-hydroxy-30;-para-phenylbenzoyloxy-lc~-cyclo-pantyl acetic acid ~-lactone and ~-)-2~-(3'-deutero-3'B-hydroxy-4',4'-dimethyl-trans-1l-octeni~-5~-hydroxy~3u-para-phenylbenzoyloxy-la-cyclo-pentyl acetic acid ~"lactone(inter,ediate co~pounds of formula V having a bulky aroup R7) A solution of 1.45 g of (-)-5~-hydroxy-2B-(3'-oxo-4',~' dimethyl-trans-1l-octenyl)-3~-para-phenylbenzoyl-oxy-la-cyclopentyl acetic acid ~-lactone in 8 ml of absolute dimethoxyethane is added dropwise to a suspension of 2.25 g of zinc borodeuteride in 20 ml of absolute dimethoxyethane at -15C in a nitrogen atmosphere.
Stirring is subse~uently effected at 3 to 5C for 3.5 - hours and at 5 to 10~ for one hour. The mixture is then again cooled to -15C and 3 ml of an aqueous 10% (w/v) sodium hydrogen tartrate solution are slo~ly added. The mixture is extracted ~ith 2x 100 ml of ether. The organic phase is washed with 100 ml of a saturated aqueous sodium chloride solution, dried with sodium sulphate and concentrated by evaporation at reduced pressure, ~?hereby 19 - .
~~ ~ ~ 100-4361 a mixture oi the corresponding a and ~ isomers is obtained. The residue is chromatoyraphed on 50 g of neutral silicagel, whereupon the ~- and then the ~-isomer is eluted ~ith chloroform (5% ethyl acetate).
a-isomer:
Thin layer chromatography (Silica gel):
Methylene chloride (5% acetic ester) Rf = 0.4, M.Pt.
` IR (methylene chloride) inter alia bands at:
3500, 1770, 1710, 1660 cm 1 ~-isomer:
Thin layer chromatography (Silica gel):
Methylene chlorlde (5% acetic ester) Rf = 0.3.
Spectral data approximately as for a-isomer.
The abo~e mentioned (-)a isomer is reacted further in step b) ~hrough to step f) yielding optically pure products as follows:-b) 2B-(3'-deutero-3'a-hydrox~y-4',4~-dimethyl-trans-~-octenyl)-3~,5a-dihydroxy-la-cyclopentyl acetic acid ~-lactone (compound of formula:V, wherein R5 = H).
A solution of 104 mg of sodium in 5.2 ml of absolute methanol is added at room temperature to a solution of 2.5 g of 2B-(3'-deutero-3'a-hydroxy-4',4'-dimethyl-trans-l'-octenyl)-5a-hydroxy-3a-para-phenyl-2i benzoyloxy-l~-cyclopentyl acetic acid ~-lactone in 104 ml of absolute methanol at room temperature. After 5 hours, the mix~ure is cooled to 10C and 6.3 ml of tartaric . - 20 -10'3~03Z 100-43Gl acid solution in methanol are added. The mixture is subsequently concentrated by evaporation at reduced pressure and the residue is taken up in 250 Irl of methyl~ne chloride. The organic phase is washed ~ith 100 ml of saturated aqueous sodium chloride solution, is dried with sodium sulphate and concentrated by evaporation at reduced pressure. The residue is chromatographed on 150 g of silicagel. The compound is elu~ed with ben7ene (20~ acetone). M.Pt. 82 - 84C.
c) 2~-(3'-deutero-3`c;-hvdroxy-4'l4'-dimethyl-trans~
octenyl)-3c;,5c[-dihydroxy-l~x-cyclopentyl acetic acid 2r-lactone-3,3'-bistetrahydropvranyl ether.
(Compound of formula V with acid sen~itive protecting groups).
A solution of 1~6 g of 2~-(3'-deutero-3'a-hydroxy-4',4'-dimethyl-trans-1'-octenyl)-3a,5c~-dihydroxy-lc~-cyclopentyl acetic acid ~-lactone, 31 mg of p-toluene sulphonic acid monohydrate and 1.33 g of 3,4-dihydro-2H-pyrane in 103 ml of absolute toluene is produced at -10C and is then allowPd to warm to room temperature.
After one hour, the solution is washed with 50 ml of 109 (W/V) aqueous potassium bicarbonate solution and twice with 100 ml of saturated aqueous sodium chloride solution.
The organic phase is dried with sodium sulphate and concentrated by evaporation at reduced pressure. The ~0'~?5~3Z loo-~ 3Gl s~ight:Lv yello~ oily resid~le is cllroma~ographed from 120 g of silicagel with toluene (+5~ acetone), whereupon the pure title compound is isolated.
Thin layer chromatography (toluene; acetone; 2:1) Rf = 0.7 (Silica gel) IR (methylene chloride) inter alia bands at 1770 cm 1.
d) 2~-(3'-deutero-3'~-hydroxy-4',4'-dimethvl-trans-~-octenyl)-3a,5a-dihydroxy-1~-cyclopentyl-acetaldehyde-~-lactol-3l3~-bis tetrahydropyranyl ether (Compound of formula III) 8.73 ml of diisobutylaluminium hydride are slowly ; added dropwise to a stirred solution of 2.43 g of 2B-~3'-deutero-3'~-hydroxy-4',4'-dimethyl-trans-1'-octenyl)-3a,5a-dihyclroxy-1-cyclopentyl acetic acid ~-lactone-
IR 3600, 1700 cm YAMPLE 10. 15-Deutero-2-ethylene-16,16-dimethyl-9~,lla, 15R-trihydroxy-prosta-5cis,13trans-dienoic acid.
IR 3400, 1690 cm 1.
EXA~PLE 11: 15-Deutero-2-ethylene-16,16-dimethyl-11~,15R-dihydroxy-9-keto-prosta-5cis,13trans-dienoic acid.
20 IR 3400, 1740-- 1730, 1700 - 1680 cm EY~IPLE 12: 15-Deutero-2-ethylene-16,16-dimethyl-15R-hydroxy-9-keto-prota-5cis,10,13trans-trienoic acid~
IR 3600, 1710 - 1685 cm ~0~503~ 100-43~1 ~XArlPT~ 13: 16-n butyl-15-deutero-2,3-(-)-trans-methylene-9~ 15S-trihydroxy- -prosta-5cis,13trans dienoic acid IR 3550 - 3350, 1715 - 1680 cm EY~lPLE 14: 16-n-butyl-15-deutero-11~,15S-dihydroxy-9-keto-2,3-(-)-trar,s-methylene-prosta-5cis, 13trans-dienoic acid.
IR 3550 - 3350, 1745 - 1690 cm EXAMPLE 15: 16-n-butyl-15-deutero-15S-hydroxy-9-keto-(2,3)-(-)-trans-methylene-prosta-5cis,10,13 trans-trienoic acid.
IR 3600, 1745 - 1690 cm EXAMPLE 16: 15-Deutero-lla,15R-dihydroxy-9-keto-16R-methyl-2,3-(-)-trans-methylene-prostanoic acid.
IR 3600 - 3300, 1740 - 1690 em EYAMPLE 17: 15-Deutero-lla,15R-dihydroxy-9-keto-16R-methyl-2,3-(-)-trans-methylene-prosta-5cis-enoic acid.
IR 3600 - 3350j 1735 - 1685 em EXAMPLE 18: 15-Deutero-11~,15R-dihydroxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-5cis, 13trans dienoic acid methyl ester.
IR 3600 - 3400, 1750 - 1700 cm ~0~5032 100-~361 EXAMPLE 19: 15-Deutero-16jl6-dimethyl-9~ a,lSR-trihydro~y--__ _ 17 t 18/19,20-tetranor-16-(3' trifluoromethyl-phenoxy)-2,3-(-)-trans-methylene-prosta--5cis, 13trans-dienoic acid.
IR 3500 - 3300, 1730 - 1670 cm EXA~LE 20: 1-Descarboxy-15-deutero 16,16--dimethyl-2-(5'-tetrazolyl)-9a,11a,15R-trihydroxy-17,18, 19,20-tetranor-16-(3'-trifluoromethylphenoxy)-prosta-5cis,13trans-dienoic acid.
IR 3500 - 3300 cm EXAMPLE 21: 15-Deutero-lla,15 R -dihydroxy-16,16-dimethyl-2,3-(-)-trans-methylene-9-keto-17,18,19,20-tetranor-16-(3'-trifluoromethylpheno~y)-prosta-5cis,13trans-dienoic acid.
IR 3500 - 3300, 1760 - 1720, 1720 - 1670 cm EXAMPLE 22: 15-Deutero-9a~11a,15S-trihydroxy-prosta-5cis, 13trans-dienoic acid lysergyl ester.
IR 3550 - 3400, 1740 (broad).
EXAMPLE 23: 15-Deutero-15S-hydroxy-ll~imidazol-l'-yl-9-keto-prosta-5cis,13trans-dienoic acid (l'-dècanyl) ester.
IR 3550 - 3350, 1740, 1720 cm 100-~36l F.XA~IPLE 24: 15-Deutero-15S-hydroxy~ imida~ol -l'-yl-9-keto-prosta-13-trans-enoic acid lysergyl ester.
IR 3500 - 3400, 1745, 1725, 1505 cm EXA~IPLE 2_: 15-Deutero~ ,15S-dihydroxy-9-keto-prosta-13trans-enoic acid lysergyl ~mide.
IR (CH2C12 + 1% CH30H) 3400 ~broad), 1745, 1665, 1525 cm EXAMPLE_ 26: 15-Deutero-16,16-dimethyl-9a,11a,15R-trihydroxy-prosta~5cis,13trans~dienoic acid IR 3650 - 3300, 1750 - 1700 cm EX~PLE 27: 15-Deutero-lla,15R-dihydroxy-16,16-dimethyl 9~keto-prosta-5cis,13trans-dienoic acid IR 3600 - 3300, 1760 - 1710, 1710 - 1630 cm EXAMPLE 28: (~)-15-Deutero-15~^hydroxy--9-ketoprostanoic acid.
IR 3550, 1760 - 1700 cm EXAMPLE 29: ~+)-15-Deutero-17,18,19,20-tetranor-16-[3'-tri-fluoromethylphenoxy]-9a,11a,15~-hydroxy-pros'a--5cis,13trans-dienoic acid.
IR 36Q0, 3350, 1710 cm EXAMPLE 30: 15-Deutero-11~,15R-dihydroxy-9-keto-16R-methyl-prosta-5cis enoic acid methyl ester.
IR 3700 - 3300, 1740 cm 1.
-- 1~ --~0~ 50~2 loo - ~ 3Gl ExAr~lPLE 31: 15-Deutero-11~,15S~dihydroxy-9-keto-prost2-5cis,13trans-dienoic acid lysergyl ester.
IR 1740 ~broad) cm Preparation of starting materials, e.g. for Example 1.
a) (-)-2R-~3'~deutero-3'a-hvdroxv~4r,4'-dimethyl-trans-1'-OCteIlyl ~ -50;-hydroxy-30;-para-phenylbenzoyloxy-lc~-cyclo-pantyl acetic acid ~-lactone and ~-)-2~-(3'-deutero-3'B-hydroxy-4',4'-dimethyl-trans-1l-octeni~-5~-hydroxy~3u-para-phenylbenzoyloxy-la-cyclo-pentyl acetic acid ~"lactone(inter,ediate co~pounds of formula V having a bulky aroup R7) A solution of 1.45 g of (-)-5~-hydroxy-2B-(3'-oxo-4',~' dimethyl-trans-1l-octenyl)-3~-para-phenylbenzoyl-oxy-la-cyclopentyl acetic acid ~-lactone in 8 ml of absolute dimethoxyethane is added dropwise to a suspension of 2.25 g of zinc borodeuteride in 20 ml of absolute dimethoxyethane at -15C in a nitrogen atmosphere.
Stirring is subse~uently effected at 3 to 5C for 3.5 - hours and at 5 to 10~ for one hour. The mixture is then again cooled to -15C and 3 ml of an aqueous 10% (w/v) sodium hydrogen tartrate solution are slo~ly added. The mixture is extracted ~ith 2x 100 ml of ether. The organic phase is washed with 100 ml of a saturated aqueous sodium chloride solution, dried with sodium sulphate and concentrated by evaporation at reduced pressure, ~?hereby 19 - .
~~ ~ ~ 100-4361 a mixture oi the corresponding a and ~ isomers is obtained. The residue is chromatoyraphed on 50 g of neutral silicagel, whereupon the ~- and then the ~-isomer is eluted ~ith chloroform (5% ethyl acetate).
a-isomer:
Thin layer chromatography (Silica gel):
Methylene chloride (5% acetic ester) Rf = 0.4, M.Pt.
` IR (methylene chloride) inter alia bands at:
3500, 1770, 1710, 1660 cm 1 ~-isomer:
Thin layer chromatography (Silica gel):
Methylene chlorlde (5% acetic ester) Rf = 0.3.
Spectral data approximately as for a-isomer.
The abo~e mentioned (-)a isomer is reacted further in step b) ~hrough to step f) yielding optically pure products as follows:-b) 2B-(3'-deutero-3'a-hydrox~y-4',4~-dimethyl-trans-~-octenyl)-3~,5a-dihydroxy-la-cyclopentyl acetic acid ~-lactone (compound of formula:V, wherein R5 = H).
A solution of 104 mg of sodium in 5.2 ml of absolute methanol is added at room temperature to a solution of 2.5 g of 2B-(3'-deutero-3'a-hydroxy-4',4'-dimethyl-trans-l'-octenyl)-5a-hydroxy-3a-para-phenyl-2i benzoyloxy-l~-cyclopentyl acetic acid ~-lactone in 104 ml of absolute methanol at room temperature. After 5 hours, the mix~ure is cooled to 10C and 6.3 ml of tartaric . - 20 -10'3~03Z 100-43Gl acid solution in methanol are added. The mixture is subsequently concentrated by evaporation at reduced pressure and the residue is taken up in 250 Irl of methyl~ne chloride. The organic phase is washed ~ith 100 ml of saturated aqueous sodium chloride solution, is dried with sodium sulphate and concentrated by evaporation at reduced pressure. The residue is chromatographed on 150 g of silicagel. The compound is elu~ed with ben7ene (20~ acetone). M.Pt. 82 - 84C.
c) 2~-(3'-deutero-3`c;-hvdroxy-4'l4'-dimethyl-trans~
octenyl)-3c;,5c[-dihydroxy-l~x-cyclopentyl acetic acid 2r-lactone-3,3'-bistetrahydropvranyl ether.
(Compound of formula V with acid sen~itive protecting groups).
A solution of 1~6 g of 2~-(3'-deutero-3'a-hydroxy-4',4'-dimethyl-trans-1'-octenyl)-3a,5c~-dihydroxy-lc~-cyclopentyl acetic acid ~-lactone, 31 mg of p-toluene sulphonic acid monohydrate and 1.33 g of 3,4-dihydro-2H-pyrane in 103 ml of absolute toluene is produced at -10C and is then allowPd to warm to room temperature.
After one hour, the solution is washed with 50 ml of 109 (W/V) aqueous potassium bicarbonate solution and twice with 100 ml of saturated aqueous sodium chloride solution.
The organic phase is dried with sodium sulphate and concentrated by evaporation at reduced pressure. The ~0'~?5~3Z loo-~ 3Gl s~ight:Lv yello~ oily resid~le is cllroma~ographed from 120 g of silicagel with toluene (+5~ acetone), whereupon the pure title compound is isolated.
Thin layer chromatography (toluene; acetone; 2:1) Rf = 0.7 (Silica gel) IR (methylene chloride) inter alia bands at 1770 cm 1.
d) 2~-(3'-deutero-3'~-hydroxy-4',4'-dimethvl-trans-~-octenyl)-3a,5a-dihydroxy-1~-cyclopentyl-acetaldehyde-~-lactol-3l3~-bis tetrahydropyranyl ether (Compound of formula III) 8.73 ml of diisobutylaluminium hydride are slowly ; added dropwise to a stirred solution of 2.43 g of 2B-~3'-deutero-3'~-hydroxy-4',4'-dimethyl-trans-1'-octenyl)-3a,5a-dihyclroxy-1-cyclopentyl acetic acid ~-lactone-
3,3'-bis-tetrahydropyranyl ether in 102 ml of absolute toluene cooled to -70C in a nitrogen atmosphere. The mixture is further stirred at -70C for one hour, and subsequently 65.3 ml of tetrahydrofuran:water (2:1) are carefully added over 30 minutes. The organic phase is washed w~th 150 ml of saturated a~ueous sodium solution at room te~perature, is dried with sodium sulphate and is concentrated by evaporation at reduced pressure. The resulting title compound is obtained as viscous oil.
IR (methylene chloride) inter alia bands at: 3600, 1200 cm 10~503~ 100-4361 ~) 15-deutero-16,16-dimethyl-9~-h~droxy-lla,15~-bis-tetra--hydrop~ran~lo~y~2,3-(-) trans-methylene-prosta-5cis, l~trans-dien~ic acid (compound of formula II, A = ~.7).
380 m~ of sodium hydride are suspended in 3.8 ml of absolute di~Rthyl sulphoxide and are kept under nitrogen for 55 minutes at 75C. Upon cooling, 2.1 ml of this solution are slowly added dropwise to a prepared solution of 1.89 g of triphenylphosphonium salt of 2-~2'-bromoethyl)-(-)-trans-cyclopropyl-1-carboxylic acid in 5 ml of absolute dim.ethyl sulphoxide and are stirred under nitrogen for 45 ~,inutes to produce an ylide solution.
IR (methylene chloride) inter alia bands at: 3600, 1200 cm 10~503~ 100-4361 ~) 15-deutero-16,16-dimethyl-9~-h~droxy-lla,15~-bis-tetra--hydrop~ran~lo~y~2,3-(-) trans-methylene-prosta-5cis, l~trans-dien~ic acid (compound of formula II, A = ~.7).
380 m~ of sodium hydride are suspended in 3.8 ml of absolute di~Rthyl sulphoxide and are kept under nitrogen for 55 minutes at 75C. Upon cooling, 2.1 ml of this solution are slowly added dropwise to a prepared solution of 1.89 g of triphenylphosphonium salt of 2-~2'-bromoethyl)-(-)-trans-cyclopropyl-1-carboxylic acid in 5 ml of absolute dim.ethyl sulphoxide and are stirred under nitrogen for 45 ~,inutes to produce an ylide solution.
4 ml of the ylide solution are added at 20C to a prepared solution of 980 mg of 2~-~3'-deutero-3'~-hydroxy-4r,4'-dimethyl-trans-l'-octenyl)-3~,5~-dihydroxy-1~-cyclopentyl-acetaldehyde-~-lactol-3,3'-bis-tetrahydropyran~l ether in 3 ml of absolute dimethyl sulphoxide and 3 ml of absolute tetrahydrofuran. The reaction mixture is kept for 30 minutes at 55C. Upon the addition oi another 4 ml of ylide solution, stirring is effected for another l.S hours at 55C. The cooled reaction mixture is poured into lOn g of ice, the aqueous phase is adjusted to pH
3-4, and is eYtracted thrice with chloroform. The organic - phase is washed, dried and concentrated by evaporation at reduced pressure. The resulting crude product is chromato~raphed on 100 g of silicagel with chloroform ~05~503.~
100-~3~1 with I-5R methanol, whereupon the desired compound is obtained.
IR ~methylene chloride) inter alia bands at: 3600, 3500, 16~5 cm f) 15-deutero-16,16-dimethy]-9-keto-11~,15~-bis-tetra-hydropyranyloxy-2,3~ -trans-methylene-prosta-5cis, 13trans-dienoic acid tert.~butyldimethyl silyl ester.
To 460 mg of 15-deutero-16,16-dimethyl-9~-hydroxy-lla,15~-bis-tetrahydropyran~loxy-2,3-(-)-trans-methylene-prosta-5cis,13trans-dienoic acid in 4.5 ml of absolute toluene, 137 mg of tert.-butyldimethyl chlorosilane are added under nitrogen to form the corresponding silyl ester.
The reaction solution is cooled to 0 and g3 mg of tri-ethylamine in 9 ml of absolute toluene are added. After stirring at 4 hours at room temperature, the reaction mixture is cooled to -25C and is siowly added dropwise to a solution of 500 mg of N-chloro-succinimide in 19 ml of absolute toluene and 0.33 ml of dimethylsulphide ~ during the course of the next 30 minutes. After a further 3 hours 1 ml of triethylamine in 5 ml of pentane are added dropwise. The mixture is stirred for 25 minutes at room temperature and ~Jorked up with ether/water to give the desired starting rnaterial.
In analogous manner to that described above, prostaglandins are obtained from the following compounds - 2~ -~0~50~ 0-~361 of formula ~, wherein R4 and R5 are ~oth hydrogen deriveo from the c~orresponding 3-para-phenylbenzoyl and 3-benzoyl derivatives which are then converted into their correspon~lna 3,3'-bis-tetrahydropyranyl ethers.
ba)*2~-(3'-deutero-3'B-hydroxy-4',4'-dimethyl-trans-1;-octenyl)-30,5a-dihydroxy-la-cyclopentyl acetic acid ~-lactone.
- bb)~2B-(3'-deutero-3'a-hydrOxy-trans-l'-octenyl)-3a,5a~dihydrox~r-la-cyclopentyl acetic acid Y
lâctone.
bc)*2~-(3l-deutero-3lB-hydroxy-trâns~
octenyl)-3a.,5a-dihydroxy-la-cyclopentyl acetic acid Y
lactone.
bd) 2~-(3'-deutero~3'a-hydroxy-4'-methyl-trans-1-octenyl)-3a,5a-dihydroxy-la-cyclopentyl acetic acid ~lactone.
be)~2~-(3~-deutero-3l~-hydroxy-4'-methyl-trâns-l-octenyl3 3a,5a-dihydroxy-la-cyclopentyl acetic acid ~-lactone.
bf)~2~-(3'-deutero-4,~-dimeth~1-3'a-hydroxy-trans-1~-octenyl)-5a-hydroxy-la-cyclopent-3^enyl acetic acid ~lactone.
bg) 2B-(4-n-butyl-3'-deutero-3'S-hydroxy-trans-l'-octenyl)-3a,5a-dihydroxy-la-cyclopenty' acetic acid ~-lactone.
bh) 2~ -n-butyl-3'-deutero 3'S-hydroxy-trans-l-octenyl~-5a-hydroxy-la-cyclopent-3-enyl acetic acid a-lactone.
lO~ 03~ loo-~ 361 bi) 2~~(3'~deutero~3'R--hydroxy-4R-Incthyl~trans-l'-OCtenyl)-3a~a-diny~roxy-la-cyclopentyl acetic acid ~-lactone.
bj) 2p-(3'-deutero-3'R-hydroxy-4'-mcthyl~4'-[3"-trifluoro-methylphenoxy]~trans-l-pentenyl)-3a,5a-dihydroxy-la-cyclopentyl acetic acid ~ lactone.
bk) 2B~(3'~deutero-3'S-hydrQxy-trans~l'-octenyl)-3a,5a-dihydroxy-l-cyclopen4yl acetic acid ~-lactone.
bl) 2~-(3'-deutero-3'S-'nydroxy-trans-l'-octenyl)-5a-hydroxy-l~-cyclopent-3-enyl acetic acid ~-lactone.
bm)*2~-(3'~deutero-3'~-hydroxy-octyl~-5a-h~rdroxy-la-cyclo-pentyl acetic acid ~~lactone.
- bn) 2B~(3'-deutero-3'~-hydroxy~~'~(3"-trifluoromethyl-phenoxy3-trans-1-butenyl)-3a,5~~dihydroxy-la-cyclo-pentyl acetic acid ~-lactone.
* obtained in (+) racemic form and in 3'R or 3'S optically active form. ~ompounds bd) and be) may be obtained as ~he 4'a-methyl isomer or the 4'~-methyl isomer.
10~503Z ~ ~J~
E~A~IPI,E 32: 15-Deutero-~n-h~d-o~ ,15~-bis-tetrah~dro-_______________~____ ________________________ ~ran~lox~-~rosta-5cis,13trans-d~enoic_acid l~ser~ l_ester lstarting material for Example 22) a) ca. 275 mg of 15-deutero-9~-hydrox~r-11~,155-bis-tetra-h~rdrop~Tranyl~xyprosta-5cis,13trans-dienoic ~cid is reacted with 167 mg of 2,2-dithiop~rridine and 199 mg of triphenyl-phosphine in 5 ml of xylene at 20 for 24 hours. After evaporation of the solvent, the residual oil is chromato-graphed on "Sephadex LH20"* using methylene chloride + 2~
methanol to afford the corresponding 2-thiopyridyl ester.
b) 190 mg of 15-deutero-9~-hydroxy-11~,15S-bis-tetrahydro-pyranyloxyprosta-5cis,13trans-aienoic acid 2-thiopyridyl ester are reacted with 90 mg of lysergol in 5 ml of tetrahydrofuran at 20C for 24 hours. The reaction mixture is worked up on "Sephadex LH20"* with methylene chloride +
0.5% methanol to obtain the title compound.
The starting materials for Examples 25 an~ 31 may be obtained in analogous manner using the appropriate starting materials.
*Trademark for macroscopic beads of highly cross-linked polysaccharide (derived from dextran); used in chromatography.
B
~O~S~3~ 10~-4361 EXA~I~LF, 33~ Deutero~i5S-te~rahydro~ran~loxv-l la-imida7O-i'_yl-9 keto-,~rosta-13.rans-enoic acid lyser~l ester ___ __ _~_ _______ [starting material for Example 24]
A solution of 180 mg of 15-deutero-15S-tetrahydro-pyranyloxy-9-ke~o-prosta-10,13trans-dienoic acid in 4 ml of absolute dimethyl formamide may be reacted with 76 mg of carbonyldiimidazole and stirred under nitrogen for 3.5 hours. ca. 145 mg of finely powdered lysergol as well as a catalytic amount of freshly prepared sodium imidazole-tetrahydrofuran solution are added. After 7 days stirring at room temperature the solvent is evaporated to room temperature and the oily residue is chromatographed on Sephadex LH20 with methylene chloride with the addition of 1% methanol to yield the title compound.
The starting material for Example 23 may be made in an analogous manner.
3-4, and is eYtracted thrice with chloroform. The organic - phase is washed, dried and concentrated by evaporation at reduced pressure. The resulting crude product is chromato~raphed on 100 g of silicagel with chloroform ~05~503.~
100-~3~1 with I-5R methanol, whereupon the desired compound is obtained.
IR ~methylene chloride) inter alia bands at: 3600, 3500, 16~5 cm f) 15-deutero-16,16-dimethy]-9-keto-11~,15~-bis-tetra-hydropyranyloxy-2,3~ -trans-methylene-prosta-5cis, 13trans-dienoic acid tert.~butyldimethyl silyl ester.
To 460 mg of 15-deutero-16,16-dimethyl-9~-hydroxy-lla,15~-bis-tetrahydropyran~loxy-2,3-(-)-trans-methylene-prosta-5cis,13trans-dienoic acid in 4.5 ml of absolute toluene, 137 mg of tert.-butyldimethyl chlorosilane are added under nitrogen to form the corresponding silyl ester.
The reaction solution is cooled to 0 and g3 mg of tri-ethylamine in 9 ml of absolute toluene are added. After stirring at 4 hours at room temperature, the reaction mixture is cooled to -25C and is siowly added dropwise to a solution of 500 mg of N-chloro-succinimide in 19 ml of absolute toluene and 0.33 ml of dimethylsulphide ~ during the course of the next 30 minutes. After a further 3 hours 1 ml of triethylamine in 5 ml of pentane are added dropwise. The mixture is stirred for 25 minutes at room temperature and ~Jorked up with ether/water to give the desired starting rnaterial.
In analogous manner to that described above, prostaglandins are obtained from the following compounds - 2~ -~0~50~ 0-~361 of formula ~, wherein R4 and R5 are ~oth hydrogen deriveo from the c~orresponding 3-para-phenylbenzoyl and 3-benzoyl derivatives which are then converted into their correspon~lna 3,3'-bis-tetrahydropyranyl ethers.
ba)*2~-(3'-deutero-3'B-hydroxy-4',4'-dimethyl-trans-1;-octenyl)-30,5a-dihydroxy-la-cyclopentyl acetic acid ~-lactone.
- bb)~2B-(3'-deutero-3'a-hydrOxy-trans-l'-octenyl)-3a,5a~dihydrox~r-la-cyclopentyl acetic acid Y
lâctone.
bc)*2~-(3l-deutero-3lB-hydroxy-trâns~
octenyl)-3a.,5a-dihydroxy-la-cyclopentyl acetic acid Y
lactone.
bd) 2~-(3'-deutero~3'a-hydroxy-4'-methyl-trans-1-octenyl)-3a,5a-dihydroxy-la-cyclopentyl acetic acid ~lactone.
be)~2~-(3~-deutero-3l~-hydroxy-4'-methyl-trâns-l-octenyl3 3a,5a-dihydroxy-la-cyclopentyl acetic acid ~-lactone.
bf)~2~-(3'-deutero-4,~-dimeth~1-3'a-hydroxy-trans-1~-octenyl)-5a-hydroxy-la-cyclopent-3^enyl acetic acid ~lactone.
bg) 2B-(4-n-butyl-3'-deutero-3'S-hydroxy-trans-l'-octenyl)-3a,5a-dihydroxy-la-cyclopenty' acetic acid ~-lactone.
bh) 2~ -n-butyl-3'-deutero 3'S-hydroxy-trans-l-octenyl~-5a-hydroxy-la-cyclopent-3-enyl acetic acid a-lactone.
lO~ 03~ loo-~ 361 bi) 2~~(3'~deutero~3'R--hydroxy-4R-Incthyl~trans-l'-OCtenyl)-3a~a-diny~roxy-la-cyclopentyl acetic acid ~-lactone.
bj) 2p-(3'-deutero-3'R-hydroxy-4'-mcthyl~4'-[3"-trifluoro-methylphenoxy]~trans-l-pentenyl)-3a,5a-dihydroxy-la-cyclopentyl acetic acid ~ lactone.
bk) 2B~(3'~deutero-3'S-hydrQxy-trans~l'-octenyl)-3a,5a-dihydroxy-l-cyclopen4yl acetic acid ~-lactone.
bl) 2~-(3'-deutero-3'S-'nydroxy-trans-l'-octenyl)-5a-hydroxy-l~-cyclopent-3-enyl acetic acid ~-lactone.
bm)*2~-(3'~deutero-3'~-hydroxy-octyl~-5a-h~rdroxy-la-cyclo-pentyl acetic acid ~~lactone.
- bn) 2B~(3'-deutero-3'~-hydroxy~~'~(3"-trifluoromethyl-phenoxy3-trans-1-butenyl)-3a,5~~dihydroxy-la-cyclo-pentyl acetic acid ~-lactone.
* obtained in (+) racemic form and in 3'R or 3'S optically active form. ~ompounds bd) and be) may be obtained as ~he 4'a-methyl isomer or the 4'~-methyl isomer.
10~503Z ~ ~J~
E~A~IPI,E 32: 15-Deutero-~n-h~d-o~ ,15~-bis-tetrah~dro-_______________~____ ________________________ ~ran~lox~-~rosta-5cis,13trans-d~enoic_acid l~ser~ l_ester lstarting material for Example 22) a) ca. 275 mg of 15-deutero-9~-hydrox~r-11~,155-bis-tetra-h~rdrop~Tranyl~xyprosta-5cis,13trans-dienoic ~cid is reacted with 167 mg of 2,2-dithiop~rridine and 199 mg of triphenyl-phosphine in 5 ml of xylene at 20 for 24 hours. After evaporation of the solvent, the residual oil is chromato-graphed on "Sephadex LH20"* using methylene chloride + 2~
methanol to afford the corresponding 2-thiopyridyl ester.
b) 190 mg of 15-deutero-9~-hydroxy-11~,15S-bis-tetrahydro-pyranyloxyprosta-5cis,13trans-aienoic acid 2-thiopyridyl ester are reacted with 90 mg of lysergol in 5 ml of tetrahydrofuran at 20C for 24 hours. The reaction mixture is worked up on "Sephadex LH20"* with methylene chloride +
0.5% methanol to obtain the title compound.
The starting materials for Examples 25 an~ 31 may be obtained in analogous manner using the appropriate starting materials.
*Trademark for macroscopic beads of highly cross-linked polysaccharide (derived from dextran); used in chromatography.
B
~O~S~3~ 10~-4361 EXA~I~LF, 33~ Deutero~i5S-te~rahydro~ran~loxv-l la-imida7O-i'_yl-9 keto-,~rosta-13.rans-enoic acid lyser~l ester ___ __ _~_ _______ [starting material for Example 24]
A solution of 180 mg of 15-deutero-15S-tetrahydro-pyranyloxy-9-ke~o-prosta-10,13trans-dienoic acid in 4 ml of absolute dimethyl formamide may be reacted with 76 mg of carbonyldiimidazole and stirred under nitrogen for 3.5 hours. ca. 145 mg of finely powdered lysergol as well as a catalytic amount of freshly prepared sodium imidazole-tetrahydrofuran solution are added. After 7 days stirring at room temperature the solvent is evaporated to room temperature and the oily residue is chromatographed on Sephadex LH20 with methylene chloride with the addition of 1% methanol to yield the title compound.
The starting material for Example 23 may be made in an analogous manner.
Claims (4)
1. A process for the production of a compound of formula I, I
wherein A is a group of formula , , , , or B is a group of formula or wherein X is hydroxy, alkoxy of 1 to 10 carbon atoms, lysergyloxy, lysergylamino or dihydrolysergylamino, and C is a prostaglandin end group other than n-pentyl, which comprises splitting off with acid an acid sensitive protecting group or groups present in a compound of formula II, II
wherein AI is A as defined above, or or wherein R4 and R5 are, independently, hydrogen or an acid sensitive protecting group, BI is B as defined above, or B6 or wherein R6 is an acid sensitive protecting group, and C is as defined above, with the proviso that there is present at least one acid sensitive protecting group.
wherein A is a group of formula , , , , or B is a group of formula or wherein X is hydroxy, alkoxy of 1 to 10 carbon atoms, lysergyloxy, lysergylamino or dihydrolysergylamino, and C is a prostaglandin end group other than n-pentyl, which comprises splitting off with acid an acid sensitive protecting group or groups present in a compound of formula II, II
wherein AI is A as defined above, or or wherein R4 and R5 are, independently, hydrogen or an acid sensitive protecting group, BI is B as defined above, or B6 or wherein R6 is an acid sensitive protecting group, and C is as defined above, with the proviso that there is present at least one acid sensitive protecting group.
2. A prostaglandin of formula I as defined in Claim 1, whenever produced by the process of Claim 1, or by an obvious chemical equivalent thereof.
3. A process for the production of 15-deu-tero-11.alpha.,15R-dihydroxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-5cis,13trans-dienoic acid witn comprises effecting acid hydrolysis of 15-deutero-11.alpha.,15.alpha.-bis-tetrahydro-pyranyloxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-5cis,13trans-dienoic acid tert.-butyldimetnyl silyl ester.
4. 15-Deutero-11.alpha.,15R-dihydroxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-5cis, 13trans-dienoic acid, whenever produced by the process claimed in Claim 3.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH825075 | 1975-06-25 | ||
| CH8250/75 | 1975-06-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1095032A true CA1095032A (en) | 1981-02-03 |
Family
ID=4337463
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA255,572A Expired CA1095032A (en) | 1975-06-25 | 1976-06-23 | Mono-deuterated, 15-hydroxyprostaglandins |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS523039A (en) |
| AT (1) | ATA460476A (en) |
| AU (1) | AU511527B2 (en) |
| BE (1) | BE843318A (en) |
| CA (1) | CA1095032A (en) |
| DD (1) | DD124727A5 (en) |
| DE (1) | DE2626582A1 (en) |
| DK (1) | DK270176A (en) |
| ES (1) | ES449147A1 (en) |
| FI (1) | FI761741A (en) |
| FR (2) | FR2316930A1 (en) |
| GB (2) | GB1560903A (en) |
| IL (1) | IL49889A (en) |
| NL (1) | NL7606709A (en) |
| NO (1) | NO762102L (en) |
| NZ (1) | NZ181264A (en) |
| PT (1) | PT65265B (en) |
| SE (1) | SE7606972L (en) |
| ZA (1) | ZA763810B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59161476U (en) * | 1983-04-14 | 1984-10-29 | 富士重工業株式会社 | Expansion valve control structure in refrigeration cycle |
-
1976
- 1976-06-14 DE DE19762626582 patent/DE2626582A1/en not_active Withdrawn
- 1976-06-16 DK DK270176A patent/DK270176A/en unknown
- 1976-06-16 FI FI761741A patent/FI761741A/fi not_active Application Discontinuation
- 1976-06-17 NO NO762102A patent/NO762102L/no unknown
- 1976-06-17 SE SE7606972A patent/SE7606972L/en unknown
- 1976-06-21 NL NL7606709A patent/NL7606709A/en not_active Application Discontinuation
- 1976-06-22 GB GB4324/79A patent/GB1560903A/en not_active Expired
- 1976-06-22 GB GB25886/76A patent/GB1560902A/en not_active Expired
- 1976-06-23 IL IL49889A patent/IL49889A/en unknown
- 1976-06-23 NZ NZ181264A patent/NZ181264A/en unknown
- 1976-06-23 ES ES449147A patent/ES449147A1/en not_active Expired
- 1976-06-23 DD DD193532A patent/DD124727A5/xx unknown
- 1976-06-23 FR FR7619091A patent/FR2316930A1/en active Granted
- 1976-06-23 BE BE168237A patent/BE843318A/en unknown
- 1976-06-23 CA CA255,572A patent/CA1095032A/en not_active Expired
- 1976-06-23 PT PT65265A patent/PT65265B/en unknown
- 1976-06-24 AT AT0460476A patent/ATA460476A/en not_active Application Discontinuation
- 1976-06-24 JP JP51073923A patent/JPS523039A/en active Pending
- 1976-06-25 AU AU15326/76A patent/AU511527B2/en not_active Expired
- 1976-06-25 ZA ZA00763810A patent/ZA763810B/en unknown
-
1977
- 1977-01-25 FR FR7701972A patent/FR2351974A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| NZ181264A (en) | 1978-07-10 |
| AU511527B2 (en) | 1980-08-21 |
| IL49889A0 (en) | 1976-08-31 |
| GB1560903A (en) | 1980-02-13 |
| FR2351974B1 (en) | 1980-08-14 |
| ES449147A1 (en) | 1977-12-01 |
| AU1532676A (en) | 1978-01-05 |
| DK270176A (en) | 1976-12-26 |
| JPS523039A (en) | 1977-01-11 |
| BE843318A (en) | 1976-12-23 |
| DE2626582A1 (en) | 1977-03-03 |
| FR2351974A1 (en) | 1977-12-16 |
| NL7606709A (en) | 1976-12-28 |
| GB1560902A (en) | 1980-02-13 |
| FR2316930B1 (en) | 1978-11-17 |
| ZA763810B (en) | 1978-02-22 |
| PT65265A (en) | 1976-07-01 |
| IL49889A (en) | 1979-11-30 |
| FR2316930A1 (en) | 1977-02-04 |
| FI761741A (en) | 1976-12-26 |
| NO762102L (en) | 1976-12-28 |
| PT65265B (en) | 1978-03-24 |
| SE7606972L (en) | 1976-12-26 |
| DD124727A5 (en) | 1977-03-09 |
| ATA460476A (en) | 1982-01-15 |
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